Poly (ADP-ribose) Polymerase (PARP; 113 kDa) is an enzyme that catalyzes the addition of ADP-ribose residues to various target proteins. The reaction requires NAD+ as substrate. As many as 18 isoforms of PARP are known. PARP1 and PARP2 are the closest relatives [60% identical in PARP1 is activated by SSB (single-strand breaks) in DNA]. ADP-ribosylation occurs at the carboxylate groups of glutamic acid or aspartic acid residues in acceptor proteins and results in the modulation of catalytic activity and protein-protein interactions of the target proteins (e.g., modulation of chromatin structure, DNA synthesis, DNA repair (Base Excision Repair or BER), transcription, and/or cell cycle progression. PARP binds to DNA single strand as well as double strand breaks. The binding of PARP to damaged DNA leads to activation of the enzyme. PARP carries out ADP ribosylation of proteins involved in DNA repair (e.g., BER) including itself. Automodification of PARP results in its release from DNA which allows the DNA repair machinery to access the DNA damage site and carry out the repair process.
Overactivation of PARP leads to necrotic cell death as a result of NAD+ and ATP depletion.
Cancer patients who have undergone radiotherapy or have been treated with chemotherapeutic agents that damage DNA (e.g. cisplatin, irinotecan, temozolomide) harbour DNA strand breaks. Activation of PARP in such cases allows the repair of the damaged DNA, thus leading to an undesirable resistance to the chemotherapeutic agents (and the consequent inefficacy). In such a scenario, treatment with a PARP inhibitor is expected to make the repair process inefficient and cause cell death.
BRCA1 and BRCA2 play an important role in HR (Homologous Recombination). DNA breaks arising during DNA replication can only be repaired by HR.
Continuous exposure of BRCA1/BRCA2 deficient cells to PARP inhibitor results in accumulation of DNA DSB followed by apoptosis (Synthetic Lethality). Triple Negative Breast Cancers (TNBC) are also acutely sensitive to PARP since they also harbor defects in the DNA repair machinery. Recently, cancer cells deficient in USP11 and endometrial cancer cells deficient in PTEN have also been shown to be sensitive to PARP inhibitors. PARP inhibitors thus have immense potential to be used for anticancer chemotherapy. [Biochem. J., (1999) 342, 249-268; Ann. Rev. Biochem., 1977, 46:95-116; E. Journal Cancer 4 6 (2010) 9-20]. Additionally, PARP has been implicated in a number of disease conditions other than cancer. These include disorders such as stroke, traumatic brain injury, Parkinson's disease, meningitis, myocardial infarction, ischaemic cardiomyopathy and other vasculature-related disorders. In animal experiments, PARP−/−mice demonstrated improved motor and memory function after CCI (Controlled Cortical Impact) versus PARP+/+ mice (J Cereb Blood Flow Metab. 1999, Vol. 19. No. 8, 835).
While attempts have been made to develop PARP inhibitors for treating cancer and other diseases, satisfactory treatment has not been achieved. Therefore, there exists an unmet need for new PARP inhibitors and treatment regimen therewith.